Navigating the aging brain: The interplay between brain malignancy and the aging microenvironment

Qianquan Li; Junyan Zhang; Jian Luo; Shi-Qing Cai; Xin Chen

doi:10.70401/acrt.2026.0038

Navigating the aging brain: The interplay between brain malignancy and the aging microenvironment

Qianquan Li

1,#

Junyan Zhang

1,#

Jian Luo

Shi-Qing Cai

1,*

Xin Chen

1,*

Affiliation +

*Correspondence to: Xin Chen, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China. E-mail: xinchen@shsmu.edu.cn
Shi-Qing Cai, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China. E-mail: sqcai@shsmu.edu.cn

Ageing Cancer Res Treat. 2027;4:202614. 10.70401/acrt.2026.0038

Received: March 31, 2026Accepted: August 28, 2026Published: August 28, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

The rising incidence of age-related brain pathologies, including brain malignancy, underscores an urgent need to understand the mechanistic interplay between aging and tumorigenesis. Historically viewed as distinct entities, brain tumors and neurodegenerative disorders are now recognized to share key biological processes, such as cellular senescence, chronic inflammation, and metabolic dysregulation. In this review, we deconstruct the existing knowledge at the intersection of cancer neuroscience and aging biology; and propose that age-related alterations in neuronal function, such as the accumulation of senescent cells, ion channel dysregulation, and neurotransmitter imbalance, are not inert background features but as active mediators of tumor progression and treatment resistance. We summarize the aged neural microenvironment, marked by a proinflammatory senescence-associated secretory phenotype (SASP) and blood-brain barrier dysfunction, underlies permissive soil for malignancy. Moreover, we highlight the emerging concept that tumors can induce a pathological aging phenotype in surrounding neurons, which in turn potentiates the observed cognitive deterioration. By framing brain tumors as products of a dysfunctional aging ecosystem, we propose therapeutic strategies that target convergent aging mechanisms through senolysis, metabolic reprogramming, and neurotransmitter modulation, may simultaneously achieve tumor control and preserve cognitive function. This integrated perspective opens new avenues for repurposing neuroactive drugs and designing interventions that address the sophisticated biology of between aging brain and maligancy.

Keywords

Aging, cellular senescence, brain tumor, cancer neuroscience, neuronal signaling, tumor microenvironment

References

1. Zhang C, Neha , Zhang J, Dhaha P, Li X, Mishra SK, et al. Aging and senescence: Key players in brain tumor progression and drug resistance. Drug Resist Updat. 2025;81:101228.

[DOI] [PubMed]
2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.

[DOI]
3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278.

[DOI]
4. Kroemer G, Maier AB, Cuervo AM, Gladyshev VN, Ferrucci L, Gorbunova V, et al. From geroscience to precision geromedicine: Understanding and managing aging. Cell. 2025;188(8):2043-2062.

[DOI] [PubMed] [PMC]
5. Winkler F, Venkatesh HS, Amit M, Batchelor T, Demir IE, Deneen B, et al. Cancer neuroscience: State of the field, emerging directions. Cell. 2023;186(8):1689-1707.

[DOI] [PubMed] [PMC]
6. Mancusi R, Monje M. The neuroscience of cancer. Nature. 2023;618(7965):467-479.

[DOI]
7. Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573(7775):539-545.

[DOI] [PubMed] [PMC]
8. Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019;573(7775):532-538.

[DOI] [PubMed]
9. Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019;573(7775):526-531.

[DOI]
10. Tetzlaff SK, Reyhan E, Layer N, Bengtson CP, Heuer A, Schroers J, et al. Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing. Cell. 2025;188(2):390-411.e36.

[DOI]
11. Sun Y, Wang X, Zhang DY, Zhang Z, Bhattarai JP, Wang Y, et al. Brain-wide neuronal circuit connectome of human glioblastoma. Nature. 2025;641(8061):222-231.

[DOI]
12. Drexler R, Drinnenberg A, Gavish A, Yalçin B, Shamardani K, Rogers AE, et al. Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling. Cell. 2025;188(17):4640-4657.e30.

[DOI]
13. Ding C, Dong J, Pan Z, Liu S, Song Q, Yang G, et al. Glioblastoma-secreted C1QL1 orchestrates tumor microtube expansion and neural synaptic pruning to drive malignant synapse formation and recurrence. Cancer Discov. 2026;16(6):1176-1199.

[DOI] [PubMed]
14. Tenchov R, Sasso JM, Wang X, Zhou QA. Aging hallmarks and progression and age-related diseases: A landscape view of research advancement. ACS Chem Neurosci. 2024;15(1):1-30.

[DOI] [PubMed] [PMC]
15. Lee J, Kim HJ. Normal aging induces changes in the brain and neurodegeneration progress: Review of the structural, biochemical, metabolic, cellular, and molecular changes. Front Aging Neurosci. 2022;14:931536.

[DOI] [PubMed] [PMC]
16. Kitchigina VF. Mechanisms of cognitive aging: Health and pathology. Neurosci Behav Physiol. 2026;56(2):288-309.

[DOI]
17. Yuan J, Cai SQ. The regulatory mechanisms of behavioral and cognitive aging. Hereditas. 2021;43(6):545-570.

[DOI]
18. Yin JA, Liu XJ, Yuan J, Jiang J, Cai SQ. Longevity manipulations differentially affect serotonin/dopamine level and behavioral deterioration in aging Caenorhabditis elegans. J Neurosci. 2014;34(11):3947-3958.

[DOI] [PubMed] [PMC]
19. Yin JA, Gao G, Liu XJ, Hao ZQ, Li K, Kang XL, et al. Genetic variation in glia–neuron signalling modulates ageing rate. Nature. 2017;551(7679):198-203.

[DOI]
20. Yuan J, Chang SY, Yin SG, Liu ZY, Cheng X, Liu XJ, et al. Two conserved epigenetic regulators prevent healthy ageing. Nature. 2020;579(7797):118-122.

[DOI]
21. Marzola P, Melzer T, Pavesi E, Gil-Mohapel J, Brocardo PS. Exploring the role of neuroplasticity in development, aging, and neurodegeneration. Brain Sci. 2023;13(12):1610.

[DOI] [PubMed] [PMC]
22. Guskjolen A, Zirlinger M. The neuroscience of aging: Shining a candle in the dark. Neuron. 2025;113(1):1.

[DOI]
23. Navakkode S, Kennedy BK. Neural ageing and synaptic plasticity: Prioritizing brain health in healthy longevity. Front Aging Neurosci. 2024;16:1428244.

[DOI] [PubMed] [PMC]
24. Costa J, Martins S, Ferreira PA, Cardoso AMS, Guedes JR, Peça J, et al. The old guard: Age-related changes in microglia and their consequences. Mech Ageing Dev. 2021;197:111512.

[DOI]
25. García-Domínguez M. Interplay between aging and glial cell dysfunction: Implications for CNS health. Life. 2025;15(10):1498.

[DOI]
26. Jiang Q, Liu J, Huang S, Wang XY, Chen X, Liu GH, et al. Antiageing strategy for neurodegenerative diseases: From mechanisms to clinical advances. Signal Transduct Target Ther. 2025;10:76.

[DOI]
27. Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev. 2018;98(1):239-389.

[DOI]
28. Gudkov SV, Burmistrov DE, Kondakova EV, Sarimov RM, Yarkov RS, Franceschi C, et al. An emerging role of astrocytes in aging/neuroinflammation and gut-brain axis with consequences on sleep and sleep disorders. Ageing Res Rev. 2023;83:101775.

[DOI] [PubMed]
29. Venkataramani V. IGSF3-mediated potassium dysregulation promotes neuronal hyperexcitability and glioma progression. Trends Cancer. 2023;9(6):457-458.

[DOI] [PubMed]
30. Zhang Y, Duan W, Chen L, Chen J, Xu W, Fan Q, et al. Potassium ion channel modulation at cancer-neural interface enhances neuronal excitability in epileptogenic glioblastoma multiforme. Neuron. 2025;113(2):225-243.e10.

[DOI]
31. Lia A, Di Spiezio A, Vitalini L, Tore M, Puja G, Losi G. Ion channels and ionotropic receptors in astrocytes: Physiological functions and alterations in Alzheimer’s disease and glioblastoma. Life (Basel). 2023;13(10):2038.

[DOI] [PubMed] [PMC]
32. von Bernhardi R, Eugenín J. Ageing-related changes in the regulation of microglia and their interaction with neurons. Neuropharmacology. 2025;265:110241.

[DOI]
33. Li X, Li Y, Jin Y, Zhang Y, Wu J, Xu Z, et al. Transcriptional and epigenetic decoding of the microglial aging process. Nat Aging. 2023;3(10):1288-1311.

[DOI] [PubMed] [PMC]
34. Segura-Collar B, Mondejar-Ruescas L, Alcivar-López D, Garranzo-Asensio M, Mata-Martinez P, Garcia-Escudero R, et al. Comprehensive immune ageing reveals TREM2/TIM3 myeloid cells drive brain immune evasion. EBioMedicine. 2025;118:105833.

[DOI] [PubMed] [PMC]
35. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.

[DOI] [PubMed] [PMC]
36. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: The path to the clinic. Nat Med. 2022;28(8):1556-1568.

[DOI]
37. Aguado J, Amarilla AA, Taherian Fard A, Albornoz EA, Tyshkovskiy A, Schwabenland M, et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging. 2023;3(12):1561-1575.

[DOI]
38. Guvatova ZG, Vakhrusheva A, Moskalev A. A receptor for glycation end products (RAGE) is a key transmitter between garb-aging and inflammaging. Ageing Res Rev. 2026;113:102919.

[DOI]
39. Raj JAT, John G, Ghanekar S, Thiruselvan GK, Shah J, Ande D, et al. RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications. Brain Res. 2025;1869:150026.

[DOI] [PubMed]
40. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286.

[DOI] [PubMed] [PMC]
41. Li F, Wu C, Wang G. Targeting NAD metabolism for the therapy of age-related neurodegenerative diseases. Neurosci Bull. 2024;40(2):218-240.

[DOI]
42. Pai P, Das I, Reddy Y, Venkidesh BS, Bhandari P, Madalageri M, et al. Targeting glioblastoma with HDAC inhibitors: Insights into hydroxamic acid-based therapeutic strategies. Acta Neuropathol Commun. 2025;14(1):9.

[DOI] [PubMed] [PMC]
43. Lv Z, Ji T, Liu J, Sun X, Liang H. Synthetic approaches and clinical applications of representative HDAC inhibitors for cancer therapy: A review. Eur J Med Chem. 2025;283:117185.

[DOI]
44. Goodell MA, Rando TA. Stem cells and healthy aging. Science. 2015;350(6265):1199-1204.

[DOI]
45. Segel M, Neumann B, Hill MFE, Weber IP, Viscomi C, Zhao C, et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature. 2019;573(7772):130-134.

[DOI] [PubMed] [PMC]
46. Guo L, Ge L, Li Y, Wang S, Li H, Wang X, et al. Age-mimicking hydrogel stiffness recapitulates the mechanical niche of the hippocampus to regulate neural stem cell senescence. Mater Today Bio. 2026;37:102985.

[DOI] [PubMed] [PMC]
47. Xu T, Zhang L, Lu X, Ji W, Chen K. Piezo1 mediates ultrasound-stimulated dopaminergic neuron protection via synaptic vesicle recycling and ferroptosis inhibition. Neurosci Bull. 2025;41(11):1924-1938.

[DOI] [PubMed] [PMC]
48. Cox TO, Devason AS, de Araujo A, Mason S, Subramanian M, Salvador AFM, et al. Intestinal interoceptive dysfunction drives age-associated cognitive decline. Nature. 2026;652(8109):442-450.

[DOI]
49. Vecchio LM, Meng Y, Xhima K, Lipsman N, Hamani C, Aubert I. The neuroprotective effects of exercise: Maintaining a healthy brain throughout aging. Brain Plast. 2018;4(1):17-52.

[DOI] [PubMed] [PMC]
50. Li Y, Tian X, Luo J, Bao T, Wang S, Wu X. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal. 2024;22(1):285.

[DOI] [PubMed] [PMC]
51. Trastus LA, d’Adda di Fagagna F. The complex interplay between aging and cancer. Nat Aging. 2025;5(3):350-365.

[DOI]
52. Wang L, Luo Y, Chen X, Wang Y, Zhang Y. The interplay of aging and cancer: Mechanisms, implications, and therapeutic strategies. MedComm Oncol. 2025;4(3):e70041.

[DOI]
53. Patel AAH, Dzanan JJ, Ali KX, Eklund EA, Alvarez SW, Raj D, et al. Ageing promotes metastasis via activation of the integrated stress response. Nature. 2026;652(8112):1339-1348.

[DOI]
54. Mastronuzzi A, Franceschi E, D’Antonio F, Bennicelli E, Berzero G, Cella E, et al. Diagnostic and predictive molecular biomarkers in brain tumors across the lifespan: An age-stratified consensus statement. J Neurooncol. 2025;176(1):95.

[DOI] [PubMed] [PMC]
55. Ashraf A, Ashraf A, Khan L, Shaikh S, Hanif F. Glioma in different life stages: A comparative analysis of adult and pediatric tumors. Hum Gene. 2025;46:201476.

[DOI]
56. Anerillas C, Abdelmohsen K, Gorospe M. Regulation of senescence traits by MAPKs. GeroScience. 2020;42(2):397-408.

[DOI]
57. Sigaud R, Stefanski A, Selt F, Kocher D, Usta D, Picard D, et al. Multi-omics dissection of MAPK-driven senescence unveils therapeutic vulnerabilities in KIAA1549:: BRAF-fusion pediatric low-grade glioma models. Sig Transduct Target Ther. 2025;10:197.

[DOI]
58. Colucci M, Sarill M, Maddalena M, Valdata A, Troiani M, Massarotti M, et al. Senescence in cancer. Cancer Cell. 2025;43(7):1204-1226.

[DOI]
59. Ma L, Yu J, Fu Y, He X, Ge S, Jia R, et al. The dual role of cellular senescence in human tumor progression and therapy. MedComm. 2024;5(9):e695.

[DOI]
60. Xiao S, Qin D, Hou X, Tian L, Yu Y, Zhang R, et al. Cellular senescence: A double-edged sword in cancer therapy. Front Oncol. 2023;13:1189015.

[DOI]
61. Tarumi W, Murai K, Nakahata Y, Masui K. The paradox of senescence in glioblastoma: SASP as an emerging cancer hallmark. Cancers. 2026;18(4):550.

[DOI] [PubMed] [PMC]
62. Carreno G, Guiho R, Martinez-Barbera JP. Cell senescence in neuropathology: A focus on neurodegeneration and tumours. Neuropathol Appl Neurobiol. 2021;47(3):359-378.

[DOI] [PubMed] [PMC]
63. La Q, Baloch A, Lo DF. Aging-driven blood–brain barrier dysfunction and its impact on CNS cancer susceptibility: A comprehensive narrative review. Aging Cancer. 2025;6(2):46-53.

[DOI]
64. Knox EG, Aburto MR, Clarke G, Cryan JF, O’Driscoll CM. The blood-brain barrier in aging and neurodegeneration. Mol Psychiatry. 2022;27(6):2659-2673.

[DOI]
65. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: Defining a path forward. Cell. 2019;179(4):813-827.

[DOI]
66. Liang J, Zang S, Wang Z, Zhang R. Cancer and aging: Complex associations and therapeutic targets. Mol Biomed. 2026;7(1):41.

[DOI] [PubMed] [PMC]
67. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22(1):78-83.

[DOI] [PubMed] [PMC]
68. Monje M, Borniger JC, D’Silva NJ, Deneen B, Dirks PB, Fattahi F, et al. Roadmap for the emerging field of cancer neuroscience. Cell. 2020;181(2):219-222.

[DOI]
69. Hanahan D, Monje M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023;41(3):573-580.

[DOI] [PubMed] [PMC]
70. Barron T, Yalçın B, Su M, Byun YG, Gavish A, Shamardani K, et al. GABAergic neuron-to-glioma synapses in diffuse midline gliomas. Nature. 2025;639(8056):1060-1068.

[DOI]
71. Taylor KR, Barron T, Hui A, Spitzer A, Yalçin B, Ivec AE, et al. Glioma synapses recruit mechanisms of adaptive plasticity. Nature. 2023;623(7986):366-374.

[DOI]
72. Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 2015;161(4):803-816.

[DOI] [PubMed] [PMC]
73. Chen P, Wang W, Liu R, Lyu J, Zhang L, Li B, et al. Olfactory sensory experience regulates gliomagenesis via neuronal IGF1. Nature. 2022;606(7914):550-556.

[DOI]
74. Krawczyk MC, Haney JR, Pan L, Caneda C, Khankan RR, Reyes SD, et al. Human astrocytes exhibit tumor microenvironment-, age-, and sex-related transcriptomic signatures. J Neurosci. 2022;42(8):1587-1603.

[DOI]
75. Chen X, Wanggou S, Bodalia A, Zhu M, Dong W, Fan JJ, et al. A feedforward mechanism mediated by mechanosensitive ion channel PIEZO1 and tissue mechanics promotes glioma aggression. Neuron. 2018;100(4):799-815.e7.

[DOI] [PubMed]
76. Chen X, Momin A, Wanggou S, Wang X, Min HK, Dou W, et al. Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity. Neuron. 2023;111(1):30-48.e14.

[DOI] [PubMed]
77. Hitomi M, Deleyrolle LP, Mulkearns-Hubert EE, Jarrar A, Li M, Sinyuk M, et al. Differential connexin function enhances self-renewal in glioblastoma. Cell Rep. 2015;11(7):1031-1042.

[DOI] [PubMed] [PMC]
78. Mulkearns-Hubert EE, Hajdari N, Hong ES, Jacobs AP, Gaboriau A, Giltner S, et al. Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis. Cell Rep. 2025;44(9):116303.

[DOI]
79. McCutcheon S, Spray DC. Glioblastoma-astrocyte connexin 43 gap junctions promote tumor invasion. Mol Cancer Res. 2022;20(2):319-331.

[DOI] [PubMed] [PMC]
80. Oliveira R, Christov C, Guillamo JS, de Boüard S, Palfi S, Venance L, et al. Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol. 2005;6(1):7.

[DOI] [PubMed] [PMC]
81. Zhao J, Wu L, Cai G, Ou D, Liao K, Yang J, et al. Targeting PGE2 mediated senescent neuron improves tumor therapy. Neuro Oncol. 2025;27(6):1491-1506.

[DOI] [PubMed] [PMC]
82. Sontheimer H. An unexpected role for ion channels in brain tumor metastasis. Exp Biol Med (Maywood). 2008;233(7):779-791.

[DOI] [PubMed] [PMC]
83. Dong W, Fekete A, Chen X, Liu H, Beilhartz GL, Chen X, et al. A designer peptide against the EAG2–Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma. Nat Cancer. 2023;4(10):1418-1436.

[DOI]
84. Pollak J, Rai KG, Funk CC, Arora S, Lee E, Zhu J, et al. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy. PLoS One. 2017;12(3):e0172884.

[DOI] [PubMed] [PMC]
85. Carlsson A. Brain neurotransmitters in aging and dementia: Similar changes across diagnostic dementia groups. Gerontology. 1987;33(3-4):159-167.

[DOI] [PubMed]
86. Strickland M, Yacoubi-Loueslati B, Bouhaouala-Zahar B, Pender SLF, Larbi A. Relationships between ion channels, mitochondrial functions and inflammation in human aging. Front Physiol. 2019;10:158.

[DOI] [PubMed] [PMC]
87. Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res. 2011;221(2):555-563.

[DOI]
88. Berry AS, Shah VD, Baker SL, Vogel JW, O’Neil JP, Janabi M, et al. Aging affects dopaminergic neural mechanisms of cognitive flexibility. J Neurosci. 2016;36(50):12559-12569.

[DOI] [PubMed] [PMC]
89. Ciampa CJ, Parent JH, Lapoint MR, Swinnerton KN, Taylor MM, Tennant VR, et al. Elevated dopamine synthesis as a mechanism of cognitive resilience in aging. Cereb Cortex. 2022;32(13):2762-2772.

[DOI] [PubMed] [PMC]
90. Ossola P, Gerra ML, Luviè L, Piacente A, Marchesi C, Schoretsanitis G, et al. Effect of age on the response to serotonergic and noradrenergic antidepressants: A systematic review, meta-regression and individual participant data pooled analysis. J Psychiatr Res. 2025;183:133-143.

[DOI]
91. Yang Y, Yang C, Chen X, Jiang Y, Lei X, Ma K, et al. Long-range cholinergic input promotes glioblastoma progression. Cancer Cell. 2025;43(11):2089-2105.e10.

[DOI]
92. Mursaleen M, Tahir M, Suleman MU, Tabassum SN, Khalil U. The dopamine paradox in glioblastoma oncology: Methylxanthine therapy against nicotine-driven pathogenesis. Ann Med Surg. 2025;87(11):6928-6930.

[DOI]
93. Karmakar S, Lal G. Role of serotonergic system in regulating brain tumor-associated neuroinflammatory responses. Methods Mol Biol. 2024;2761:181-207.

[DOI]
94. Dong Z, Luo Y, Yuan Z, Tian Y, Jin T, Xu F. Cellular senescence and SASP in tumor progression and therapeutic opportunities. Mol Cancer. 2024;23(1):181.

[DOI]
95. Salam R, Saliou A, Bielle F, Bertrand M, Antoniewski C, Carpentier C, et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat Commun. 2023;14(1):441.

[DOI] [PubMed] [PMC]
96. López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab. 2023;35(1):12-35.

[DOI]
97. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: Senolytics and senomorphics. FEBS J. 2023;290(5):1362-1383.

[DOI] [PubMed]
98. Montgomery MK, Kim SH, Dovas A, Zhao HT, Goldberg AR, Xu W, et al. Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression. Cell Rep. 2020;31(2):107500.

[DOI] [PubMed] [PMC]
99. de Rezende VL, de Aguiar da Costa M, Martins CD, Mathias K, Gonçalves CL, Barichello T, et al. Systemic rejuvenating interventions: Perspectives on neuroinflammation and blood–brain barrier integrity. Neurochem Res. 2025;50(2):112.

[DOI]
100. Sharma D, Kumar R. Breaking barriers: The role of NETosis in blood-brain barrier leakage and age-related cognitive decline. Explor Neurosci. 2024;3(5):375-381.

[DOI]
101. Takata F, Nakagawa S, Matsumoto J, Dohgu S. Blood-brain barrier dysfunction amplifies the development of neuroinflammation: Understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci. 2021;15:661838.

[DOI] [PubMed] [PMC]
102. Ximerakis M, Holton KM, Giadone RM, Ozek C, Saxena M, Santiago S, et al. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types. Nat Aging. 2023;3(3):327-345.

[DOI]
103. Conboy MJ, Conboy IM, Rando TA. Heterochronic parabiosis: Historical perspective and methodological considerations for studies of aging and longevity. Aging Cell. 2013;12(3):525-530.

[DOI]
104. Farinas A, Rutledge J, Bot VA, Western D, Ying K, Lawrence KA, et al. Disruption of the cerebrospinal fluid-plasma protein balance in cognitive impairment and aging. Nat Med. 2025;31(8):2578-2589.

[DOI] [PubMed] [PMC]
105. Piehl N, van Olst L, Ramakrishnan A, Teregulova V, Simonton B, Zhang Z, et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell. 2022;185(26):5028-5039.e13.

[DOI] [PubMed] [PMC]
106. Vun J, Iqbal N, Jones E, Ganguly P. Anti-aging potential of platelet rich plasma (PRP): Evidence from osteoarthritis (OA) and applications in senescence and inflammaging. Bioengineering (Basel). 2023;10(8):987.

[DOI] [PubMed] [PMC]
107. Rando TA, Brunet A, Goodell MA. Hallmarks of stem cell aging. Cell Stem Cell. 2025;32(7):1038-1054.

[DOI]
108. Higgins-Chen AT, Thrush KL, Levine ME. Aging biomarkers and the brain. Semin Cell Dev Biol. 2021;116:180-193.

[DOI]
109. Aging Biomarker Consortium, Jia YJ, Wang J, Ren JR, Chan P, Chen S, et al. A framework of biomarkers for brain aging: A consensus statement by the Aging Biomarker Consortium. Life Med. 2023;2(3):lnad017.

[DOI] [PubMed] [PMC]
110. Lee DH, Lee P, Seo SW, Roh JH, Oh M, Oh JS, et al. Neural substrates of cognitive reserve in Alzheimer’s disease spectrum and normal aging. Neuroimage. 2019;186:690-702.

[DOI] [PubMed]
111. Ruetz TJ, Pogson AN, Kashiwagi CM, Gagnon SD, Morton B, Sun ED, et al. CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells. Nature. 2024;634(8036):1150-1159.

[DOI]
112. Buckingham SC, Campbell SL, Haas BR, Montana V, Robel S, Ogunrinu T, et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med. 2011;17(10):1269-1274.

[DOI] [PubMed] [PMC]
113. Simon M, von Lehe M. Glioma-related seizures: Glutamate is the key. Nat Med. 2011;17(10):1190-1191.

[DOI]
114. Anastasaki C, Mu R, Kernan CM, Li X, Barakat R, Koleske JP, et al. Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth. Neuron. 2025;113(21):3582-3600.e7.

[DOI] [PubMed] [PMC]
115. Huang X, Taylor MD. Glutamate promotes glioma growth via a non-excitable, receptor tyrosine kinase-mediated mechanism. Neuron. 2025;113(21):3493-3495.

[DOI]
116. Tsai JJ, Wu T, Leung H, Desudchit T, Tiamkao S, Lim KS, et al. Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings. Acta Neurol Scand. 2018;137(4):378-391.

[DOI] [PubMed]
117. Monje M. The neuroscience of brain cancers. Neuron. 2025;113(17):2734-2739.

[DOI]
118. Lange F, Weßlau K, Porath K, Hörnschemeyer MF, Bergner C, Krause BJ, et al. AMPA receptor antagonist perampanel affects glioblastoma cell growth and glutamate release in vitro. PLoS One. 2019;14(2):e0211644.

[DOI] [PubMed] [PMC]
119. Xi H, Jan LY. Targeting potassium channels in cancer. J Cell Biol. 2014;206(2):151-162.

[DOI]
120. Kapogiannis D, Manolopoulos A, Mullins R, Avgerinos K, Delgado-Peraza F, Mustapic M, et al. Brain responses to intermittent fasting and the healthy living diet in older adults. Cell Metab. 2024;36(8):1900-1904.

[DOI] [PubMed] [PMC]
121. Babygirija R, Han JH, Sonsalla MM, Matoska R, Calubag MF, Green CL, et al. Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer’s disease. Nat Commun. 2025;16(1):7147.

[DOI] [PubMed] [PMC]
122. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16(3):129-137.

[DOI] [PubMed]
123. Vecchio LM, Meng Y, Xhima K, Lipsman N, Hamani C, Aubert I. The neuroprotective effects of exercise: Maintaining a healthy brain throughout aging. Brain Plast. 2018;4(1):17-52.

[DOI] [PubMed] [PMC]
124. Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17(2):e12750.

[DOI]
125. Carro E, Nuñez A, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci. 2000;20(8):2926-2933.

[DOI] [PubMed] [PMC]
126. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-659.

[DOI]
127. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20(10):2580-2590.

[DOI] [PubMed]
128. Speisman RB, Kumar A, Rani A, Foster TC, Ormerod BK. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav Immun. 2013;28:25-43.

[DOI] [PubMed] [PMC]
129. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999;96(23):13427-13431.

[DOI] [PubMed] [PMC]
130. Tantillo E, Colistra A, Baroncelli L, Costa M, Caleo M, Vannini E. Voluntary physical exercise reduces motor dysfunction and hampers tumor cell proliferation in a mouse model of glioma. Int J Environ Res Public Health. 2020;17(16):5667.

[DOI] [PubMed] [PMC]
131. Gehring K, Stuiver MM, Visser E, Kloek C, van den Bent M, Hanse M, et al. A pilot randomized controlled trial of exercise to improve cognitive performance in patients with stable glioma: A proof of concept. Neuro-Oncology. 2020;22(1):103-115.

[DOI]
132. Vo AH, Libmann M, Carson D, Wang K, Puri S, Butowski N, et al. A scoping review of exercise oncology in the primary brain tumor patient-caregiver dyad. Curr Oncol. 2026;33(4):193.

[DOI] [PubMed] [PMC]
133. Ye SW, Song SD, Liu XJ, Luo Y, Cai SQ. A small-molecule screen identifies novel aging modulators by targeting 5-HT/DA signaling pathway. Aging Cell. 2025;24(3):e14411.

[DOI]
134. Wang X, Wang Y, Xie F, Song ZT, Zhang ZQ, Zhao Y, et al. Norepinephrine promotes glioma cell migration through up-regulating the expression of Twist1. BMC Cancer. 2022;22(1):213.

[DOI] [PubMed] [PMC]
135. Minniti G, Filippi AR, Osti MF, Ricardi U. Radiation therapy for older patients with brain tumors. Radiat Oncol. 2017;12(1):101.

[DOI]
136. Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170-186.

[DOI]
137. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707-715.

[DOI]
138. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376(11):1027-1037.

[DOI] [PubMed]
139. Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018;20(2):184-191.

[DOI] [PubMed] [PMC]
140. Nayak L, Iwamoto FM. Primary brain tumors in the elderly. Curr Neurol Neurosci Rep. 2010;10(4):252-258.

[DOI]
141. Vallet-Regí M, Manzano M, Rodriguez-Mañas L, López MC, Aapro M, Balducci L. Management of cancer in the older age person: An approach to complex medical decisions. Oncologist. 2017;22(3):335-342.

[DOI]
142. Zhang S, Yuan L, Lin P, Yang G, Zhou X, Xu J, et al. Cancer neuroscience: Signaling pathways and new therapeutic strategies for cancer. Sig Transduct Target Ther. 2026;11(1):66.

[DOI] [PubMed] [PMC]
143. Ainslie AP, Klaver M, Voshart DC, Gerrits E, den Dunnen WFA, Eggen BJL, et al. Glioblastoma and its treatment are associated with extensive accelerated brain aging. Aging Cell. 2024;23(3):e14066.

[DOI] [PubMed] [PMC]
144. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.

[DOI]
145. Hanahan D. Hallmarks of cancer: Then and now, and beyond. Cell. 2026;189(8):2254-2277.

[DOI]
146. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: A new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-590.

[DOI]
147. Anastasaki C, Gao Y, Gutmann DH. Neurons as stromal drivers of nervous system cancer formation and progression. Dev Cell. 2023;58(2):81-93.

[DOI]
148. Karreman MA, Winkler F. Cancer neuroscience of brain metastasis: When in Rome, do as the Romans do. Neuron. 2025;113(17):2740-2759.

[DOI]
149. Logun M, Wang X, Sun Y, Bagley SJ, Li N, Desai A, et al. Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy. Cell Stem Cell. 2025;32(2):181-190.e4.

[DOI] [PubMed] [PMC]
150. Peng T, Ma X, Hua W, Wang C, Chu Y, Sun M, et al. Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy. Cell Stem Cell. 2025;32(4):652-669.e11.

[DOI]
151. Watanabe F, Hollingsworth EW, Bartley JM, Wisehart L, Desai R, Hartlaub AM, et al. Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma. PNAS Nexus. 2024;3(2):pgae051.

[DOI]
152. Hu JL, Todhunter ME, LaBarge MA, Gartner ZJ. Opportunities for organoids as new models of aging. J Cell Biol. 2018;217(1):39-50.

[DOI]
153. Shen X, Wang C, Zhou X, Zhou W, Hornburg D, Wu S, et al. Nonlinear dynamics of multi-omics profiles during human aging. Nat Aging. 2024;4(11):1619-1634.

[DOI] [PubMed] [PMC]
154. Wang X, Sun Q, Liu T, Lu H, Lin X, Wang W, et al. Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting. Sci Adv. 2024;10(47):eadn4306.

[DOI] [PubMed] [PMC]
155. Karimi E, Yu MW, Maritan SM, Perus LJM, Rezanejad M, Sorin M, et al. Single-cell spatial immune landscapes of primary and metastatic brain tumours. Nature. 2023;614(7948):555-563.

[DOI] [PubMed] [PMC]
156. Jeffries AM, Yu T, Ziegenfuss JS, Tolles AK, Baer CE, Sotelo CB, et al. Single-cell transcriptomic and genomic changes in the ageing human brain. Nature. 2025;646(8085):657-666.

[DOI] [PubMed] [PMC]
157. Bedbrook CN, Nath RD, Zhang L, Linderman SW, Brunet A, Deisseroth K. Lifelong behavioral screen reveals an architecture of vertebrate aging. Science. 2026;391(6790):eaea9795.

[DOI]

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Li Q, Zhang J, Luo J, Cai SQ, Chen X. Navigating the aging brain: The interplay between brain malignancy and the aging microenvironment. Ageing Cancer Res Treat. 2027;4:202614. https://doi.org/10.70401/acrt.2026.0038